Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• PCT International Publication No. WO95/10516 relates to tricyclic amide and urea compounds of the general formula ( 1.0)
• the present invention provides novel tricyclic amide compounds selected from the group consisting of:
• This invention includes the above compounds in the amorphous state or in the cyrstalline state.
• compounds of this invention include compounds selected from the group consisting of: Compounds 1.0, 2.0, 3.0, 5.0, 6.0, 7.0, 7.0A, 8.0, 8.0A, 9.0, 10.0, 1 1.0, 12.0, 13.0, 14.0, 15.0, 16.0, and 17.0, or pharmaceutically acceptable salts thereof, wherein said compounds are as defined above.
• Compounds of this invention also include compounds selected from the group consisting of: Compounds 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, and 41.0, or pharmaceutically acceptable salts thereof, and wherein said compounds are as defined above.
• Compounds of this invention also include compounds selected from the group consisting of: (+)-enantiomer
• compounds of this invention include compounds selected from the group consisting of: Compounds 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0 and 69.0, or pharmaceutically acceptable salts thereof, wherein said compounds are as defined above.
• Preferred compounds include the 3,7,8-trihalo compounds having a (-)-optical rotation.
• Preferred compounds also include the 3,8, 10-trihalo compounds having a (+)-optical rotation.
• 3,8, 10-trihalo compounds having a (+)-optical rotation For example,
• Preferred compounds also include the 3, 10-dihalo
• Preferred compounds also include the 3,7-dibromo-8- chloro compounds having S stereochemistry at the C- 1 1 position.
• Preferred compounds also include the 3,10-dibromo-8-chlorocompounds having R stereochemistry at the C-1 1 position.
• Preferred compounds also include Compounds 16.0, 17.0, 39.0, 40.0, 41.0, 68.0 and 69.0.
• More preferred compounds are Compounds 16.0, 39.0, 40.0, 68.0 and 69.0. Most preferred compounds are Compounds 16.0, 39.0 and 68.0. Even more preferred is Compound 39.0 or 68.0.
• this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro ; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block
• Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
• the compounds of this invention have been demonstrated to have anti-tumor activity in animal models.
• This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention.
• Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: ( 1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and
• This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment.
• this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds.
• tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancers and prostate cancers.
• lung cancer e.g., lung adenocarcinoma
• pancreatic cancers e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma
• colon cancers e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma
• this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes ⁇ i.e., the Ras gene itself is not activated by mutation to an oncogenic form ⁇ with said
• inhibition being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment.
• a mammal e.g., a human
• tyrosine kinase oncogenes e.g., neu, src, abl, lck, and fyn
• tyrosine kinase oncogenes e.g., neu, src, abl, lck, and fyn
• the compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras.
• This invention further provides a method of inhibiting ras farnesyl protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the
• the tricyclic compounds useful in the methods of this invention inhibit the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21 , by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
• solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HO Ac or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1 -hydroxy-benzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA);
• Certain compounds of the present invention may exist in different isomeric forms (e.g., enantiomers or diastereoisomers) including atropisomers (i.e., compounds wherein the
• 11-carbon atom is positioned above or below the plane of the fused beznene rings due to the presence of a 10-bromo
• the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
• salts e.g., acid addition salts.
• the pyrido-nitrogen atoms may form salts with strong acids.
• suitable acids for salt formation are
• the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
• the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• the free base forms differ from their respective salt forms
• the compounds of the present invention can be prepared by the procedures described below.
• the compound of Example 10 is obtained in the cyrstalline state.
• Those skilled in the art will appreciate that compounds obtained in the amorphous state can be obtained in the cyrstalline state by cyrstallizing the amorphous materials from solvents or solvent mixtures such as acetone, diethyl ether, ethyl acetate, ethanol, 2-propanol, tert-butyl ether, water and the like according to procedures well known in the art.
• Elemental analysis calculated - C, 45.11 ; H, 3.44; N, 7.17 found - C, 44.95; H, 3.57; N, 7.16.
• Step A
• Step A The racemic title compound of Step A is separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, using 20% iPrOH/hexane + 0.2% diethylamine), to give the (+)-enantiomer and the (-)-enantiomer of the title compound.
• Elemental analysis calculated - C, 48.81 ; H, 4.10; N, 6.57 found - C, 49.10; H, 3.79; N, 6.74.
• Elemental analysis calculated - C, 48.77; H, 3.62; N, 6.56 found - C, 48.34; H, 3.95; N, 6.84.
• the HCl salt of the title compound of Example 7 is prepared by stirring for 1 hr. with HCl/CH 2 Cl 2 , then
• Example 7 is a racemic mixture of atropisomers. Those atropisomers are separated by preparative chromatography (HPLC), using an Chiralpack AD column (5 cm ⁇ 50 cm) and 40% i-PrOH/ hexane + 0.2% diethylamine as the mobile phase to give the (+)- and (-)-enantiomers, Examples 7B and 7A, respectively.
• Example 8 The title compound of Example 8 is a racemic mixture of atropisomers. Those atropisomers are separated by preparative chromatography (HPLC), using an Chiralpack AD column (5 cm ⁇ 50 cm) and 20% i-PrOH/ hexane + 0.2% diethylamine as the mobile phase, at a flow rate of 100 mL/min., to give the (+)- and (-)-enantiomers, Examples 8B and 8A, respectively.
• HPLC preparative chromatography
• Step B 2.38 g of the title compound of Preparative Example 1 , 1.92 g of HOBT, 2.70 g of DEC, 1.56 mL of N-methylmorpholine and 50 mL of dry DMF and stir at 25°C for 24 hrs. Concentrate in vacuo, then dilute the residue with CH 2 Cl 2 . Wash with 1 N NaOH (aqueous), then with saturated NaH2PO4 (aqueous) and dry over MgSO 4 . Concentrate in vacuo to a residue and chromatograph (silica gel, 2%
• the HCl salt of the title compound of Example 9A is prepared by dissolving of the title compound in CH 2 Cl 2 , adding 6M HCl (g) in CH 2 Cl 2 , then concentrating in vacuo to give the salt.
• Example 1 1 A or the S-(-)-enantiomer (Example 1 1B) is prepared using substantially the same procedure as described for Example 2.
• the title compound of this Example is prepared using the racemic title compound from Preparative Example 9, Step F, by following substantially the same procedures as described for Example 8, Steps A-C. This compound is a racemate.
• Example 12 The title compound of Example 12 is a racemic mixture. Chromatograph 2.45 g of the compound of Example 12, using an Chiralpack AD column and 20% i-PrOH/ hexane + 0.2%
• diethylamine as the mobile phase, at a flow rate of 100
• Step E treat 10.0 g (28.0 mmol) of the product of Step B with NaBH 4 to obtain the desired product, which is used in the next step without further purification.
• Extract with CH 2 Cl 2 wash with brine, dry over Na 2 SO 4 , filter and concentrate. Purify by preparative TLC, eluting with
• Step E treat 1.75 g (5.425 mmol) of the product of Step A with NaBH 4 to obtain the desired product.
• Step B Dissolve the residue obtained in Step B in 50 mL CH 2 Cl 2 at room temperature, add 3.95 mL (5.425 mmol) of SOCl 2 and stir at room temperature overnight. Remove excess SOCl 2 and solvent under vacuum. Dissolve the residue in CH 2 Cl 2 , wash with sat'd NaHCO 3 and brine, dry over Na 2 SO 4 , filter and concentrate. Add 25 mL THF to the resultant residue, add 2.33 g (27.125 mmol) piperazine and stir at room temperature overnight. Evaporate the solvent, add CH 2 Cl 2 wash with sat'd
• Example 9 in 150 mL CH 2 Cl 2 and 200 mL CH 3 CN at room temperature. Heat the mixture to 60°C, add 10.45 g (32.6 mmol) of 1 -fluoro-4-hydroxy- 1 ,4-diazoniabicyclo[2,2,2]octane bis- (tetrafluoroborate) and heat to reflux for 4 h. Cool the mixture to room temperature, extract with CH 2 Cl 2 and 1 N NaOH. Dry the CH 2 Cl 2 layer over MgSO 4 , filter and concentrate to dryness.
• Step D treat 1.80 g (5.1 mmol) of the product of Step A. Purify the crude product by flash
• Step E treat 0.47 g ( 1.4 mmol) of the product of Step B with NaBH 4 to obtain the desired product.
• Mass spec: MH + 342.
• FPT farnesyl protein transferase
• GGPT geranylgeranyl protein transferase
• geranylgeranyltransferase from bovine brain Implications for protein prenylation specificity, Proc. Natl. Acad. Sci USA 88 : 5302-5306, the disclosure of which is incorporated herein by reference thereto).
• Human farnesyl protein transferase was also expressed in E. coli, using cDNA clones encoding both the a and b subunits. The methods used were similar to those published (Omer, C. et al., ( 1993), Characterization of recombinant human farnesyl protein transferase: Cloning, expression, farnesyl diphosphate binding, and functional homology with yeast prenyl-protein transferases, Biochemistry 32:5167-5176).
• Human farnesyl protein transferase was partially-purified from the soluble protein fraction of E. coli as described above.
• the tricyclic farnesyl protein transferase inhibitors disclosed herein inhibited both human and rat enzyme with similar potencies.
• Two forms of val 1 2 -Ha-Ras protein were prepared as substrates for these enzymes, differing in their carboxy terminal sequence. One form terminated in cysteine-valine-leucine-serine (Ras- CVLS) the other in cystein-valine-leucine-leucine (Ras-CVLL).
• Ras-CVLS is a substrate for the farnesyl protein transferase while Ras-CVLL is a substrate for geranylgeranyl protein transferase I.
• the cDNAs encoding these proteins were
• reaction mixture contained 40 mM Hepes, pH 7.5; 20 mM magnesium chloride; 5 mM dithiothreitol; 0.25 ⁇ M [ 3 H]farnesyl pyrophosphate; 10 ml Q-Sepharose-purified farnesyl protein transferase; the indicated
• DMSO methyl methoxysulfate
• SDS sodium dodecyl sulfate
• TCA cold 30% TCA
• Samples were allowed to sit on ice for 45 minutes and precipitated Ras protein was then collected on GF/C filter paper mats using a Brandel cell harvester. Filter mats were washed once with 6% TCA, 2% SDS and radioactivity was measured in a Wallac 1204 Betaplate BS liquid scintillation counter. Percent inhibition was calculated relative to the DMSO vehicle control.
• the geranylgeranyl protein transferase I assay was essentially identical to the farnesyl protein transferase assay described above, with two exceptions:
• val 12 -Ha-Ras-CVLS and val 12 -Ha-Ras-CVLL in COS monkey kidney cells Effect of farnesyl protein transferase inhibitors on Ras processing and on disordered cell growth induced by transforming Ras.
• COS monkey kidney cells were transfected by
• Cellular protein was precipitated by addition of ice-cold trichloroacetic acid and redissolved in 100 ml of SDS-electrophoresis sample buffer. Samples (5-10 ml) were loaded onto 14% polyacrylamide minigels (Novex, Inc.) and
• HEPM fibroblasts Normal human HEPM fibroblasts were planted in 3.5 cm dishes at a density of 5 ⁇ 10 4 cells/dish in 2 ml growth medium, and incubated for 3-5d to achieve confluence. Medium was aspirated from each dish and the indicator tumor cells,
• T24-BAG4 human bladder carcinoma cells expressing an activated H-ras gene were planted on top of the fibroblast monolayer at a density of 2 ⁇ 10 3 cells/dish in 2 ml growth medium, and allowed to attach overnight.
• Compound-induced colony inhibition was assayed by addition of serial dilutions of compound directly to the growth medium 24 h after tumor cell planting, and incubating cells for an additional 14 d to allow colony formation. Assays were terminated by rinsing
• IC 50 concentration of drug required to prevent the increase in tumor cell number by 50%
• Both IC 50 values were obtained by determining the density of tumor cells and mat cells by visual inspection and enumeration of cells per colony and the number of colonies under the microscope.
• the therapeutic index of the compound was quantitatively expressed as the ratio of mlC 50 /tlC 50 , with values greater than one indicative of tumor target specificity.
• Anchorage-independent growth is a characteristic of tumorigenic cell lines.
• Human tumor cells are suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor.
• the solution is overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer.
• plates are incubated for 10-16 days at 37°C under 5% CO 2 to allow colony outgrowth. After incubation, the colonies are stained by overlaying the agar with a solution of MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide,
• SCLC SCLC
• HTB 183 NCI H661
• NSCLC NSCLC ras mut. not detected
• HPAF II pancreatic K ras mutation
• MCF-7 breastcreatic ras mutation
• HBL100 breast ras mut. not detected
• Du4475 Du4475
• MB453 (breast); BT474 (breast); PC3 (prostate); DLD 1 (colon) K ras mutation; and AsPc- 1 (pancreatic) K ras mutation. Ras mutation status determined by ELISA (Oncogene Science).
• IC 50 ( ⁇ M) for each cell line was within the range of 0.04 and 3.0.
• Ras mutation status determined by ELISA (Oncogene Science). The IC 50 ( ⁇ M) for each cell line was within the range of 0.175 and 0.8.
• GGPT geranylgeranyl protein transferase
• Example 2 inhibited Ras-CVLS processing with an IC 50 value of 0.025 ⁇ M, but did not block the
• Tricyclic farnesyl protein transferase inhibitors of this invention also inhibited the growth of Ras-transformed tumor cells in the Mat assay without displaying cytotoxic activity against the normal monolayer.
• DLD- 1 human colon carcinoma cells, ATCC # CCL 221
• Tumor bearing animals are selected and
• the average % tumor inhibition for each compound of Examples 1, 2, 4, 5, 6, 7, 7A, 8B, 9, 10, 11A, 11B, 12B, 13, 14A, 16B, and 18 was 7 to 50% for a dose of 10 mg/kg p.o, and 35.4 to 83 for a dose of 50 mg/kg p.o.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 70 percent active ingredient.
• Suitable solid carriers are known in the art, e.g.
• magnesium carbonate magnesium stearate, talc, sugar, lactose.
• Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.
• Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in
• a pharmaceutically acceptable carrier such as an inert compressed gas.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compound is administered orally.
• the pharmaceutical preparation is in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
• a typical recommended dosage regimen is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to block tumor growth.
• the compounds are non-toxic when administered within this dosage range.

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• 1996
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